Therapeutic Approaches Targeting ALK, ROS1, RET, TRK and NRG1 — Jessica J Lin, MD

DR LIN: Hi everyone. I am Jessica Lin. I'm a medical oncologist at Massachusetts General Hospital. And I'm really happy to be here today to review for you the updates in therapeutic approaches targeting an array of targets listed here, ALK, ROS1, RET, TRK and NRG1. And I want to thank Neil for having me.

There is a lot to cover so we're going to jump right in. And what I'll do is take you through each of the fusion targets that I mentioned one by one. We'll start with ALK. And we're going to start specifically with the advances in metastatic ALK-positive non-small cell lung cancer and then move into the early stage surgically resected setting. To set the stage and as a quick reminder for you, we have seen the evolution of a number of effective ALK inhibitors over the years for the treatment of ALK-positive lung cancer. I have listed the FDA approved ALK inhibitors in this diagram. These, as you can see, are classified into successive generations with each higher generation of ALK inhibitors typically characterized by higher potency against ALK, increased brain penetration, and therefore improved CNS activity, and coverage of on-target ALK mutations that we know can cause resistance to the earlier-generation agents.

We have what we use as the old standard of care, initial therapy for metastatic ALK-positive lung cancer, which is crizotinib on the far left side. This is the first-generation ALK inhibitor. And then we have a number of second-generation ALK inhibitors listed in the middle, which includes ceritinib, alectinib, brigatinib and ensartinib. And then the third-generation TKI, lorlatinib.

Now I mentioned ensartinib. Briefly, ensartinib just recently received FDA approval actually in December of last year, 2024. The approval was for patients with advanced ALK-positive lung cancer. And it was based on a Phase III trial called eXALT3. This was a global randomized controlled trial that enrolled patients with TKI naïve advanced ALK-positive lung cancer. I have the schema shown here. So you can see patients were randomized 1:1 to receive either ensartinib, which is a second-generation ALK inhibitor, versus crizotinib, the first-generation ALK inhibitor, and there was no crossover allowed. And here the primary endpoint was blinded independent review committee-assessed progression-free survival.

As you can see from the Kaplan-Meier curve, this was a positive trial with a PFS hazard ratio of 0.51 in favor of ensartinib over crizotinib. The median progression-free survival with first-line use of ensartinib was 25.8 months. I'll just comment here that these are strikingly comparable progression-free survival results to what we had observed with other Phase III trials that had compared these other second-generation ALK inhibitors against crizotinib. In terms of both the hazard ratio for disease progression or death or the median progression-free survival achieved by using a second-generation ALK TKI like ensartinib or like the other ones that I've shown, alectinib, brigatinib and so forth.

Now one of the highlights from last year's ASCO meeting was the 5-year outcome update from the CROWN trial. CROWN was a Phase III randomized controlled trial that compared lorlatinib, the third-generation ALK inhibitor, against crizotinib in patients with treatment-naïve advanced ALK-positive lung cancer. PFS, by again blinded independence central review, was also the primary endpoint for this trial. And prior to last year's ASCO meeting, we had already learned that this trial met its primary endpoint at interim analysis. The hazard ratio for disease progression or death at interim analysis was 0.28 in favor of lorlatinib. And this had already led to the regular approval of lorlatinib by the FDA for metastatic ALK-positive lung cancer including as first-line therapy.

At last year's ASCO, Dr Solomon and colleagues presented the post-hoc 5-year outcome analysis from this trial with efficacy endpoints analyzed per investigator assessment. The median progression-free survival of first-line lorlatinib remains not reached. This was after 60.2 months of follow-up. And 5-year progression-free survival was 60%. Now I want to place this finding into context for you. So when we look at the Phase III ALEX trial this was the trial that compared the second-generation ALK inhibitor, alectinib, against crizotinib. The median progression-free survival there of first-line alectinib per investigator assessment was 34.8 months.

And then in the Phase III ALTA-IL trial, which compared brigatinib, another second-generation ALK inhibitor, against crizotinib, the median progression-free survival with first-line brigatinib use per investigator assessment was 30.8 months. We should acknowledge that there hasn't been a head-to-head trial directly comparing lorlatinib against a second-generation ALK inhibitor like alectinib or brigatinib.

On the right-hand side, I'm showing the time to intracranial progression Kaplan-Meier curve from the CROWN trial 5-year update. Why do we care about this? Brain metastasis represent an important challenge for patients and caregivers alike. So we always consider strongly the CNS efficacy of targeted agents and other systemic therapies. In the CROWN trial, the time to intracranial progression per investigator assessment was markedly longer for patients treated with lorlatinib compared to crizotinib. Here the hazard ratio was 0.06. The probability of being free of intracranial progression with first-line lorlatinib therapy was 92% at 5 years, which really speaks to the effective CNS penetration by lorlatinib and its ability to then protect against the development of new brain metastasis.

Given the long durations of therapy that patients are seeing now with these targeted agents, there's a lot of interest emerging in understanding some of the longer-term safety and tolerability issues. At the 5-year follow-up mark in CROWN, no new safety signals were identified with lorlatinib. And the adverse event profile was really consistent with prior reports. The most common treatment related adverse events remained hyperlipidemia, that's very common with lorlatinib therapy, edema, peripheral neuropathy, weight increase. All-cause adverse events led to treatment discontinuation of lorlatinib in 11% of patients and in 5% these adverse events were treatment related. Importantly, vigilant monitoring for adverse events and dose modification, if warranted, remains the cornerstone of optimal treatment for our patients. In the data that were presented at ASCO, I do want to remind you that when lorlatinib was dose reduced in patients within the first 16 weeks of therapy that was not found to affect its efficacy.

And then at the WCLC meeting last September 2024, we gained further insight into lorlatinib associated toxicities. In terms of their kinetics, the onset is really early on. You can see here that for hypercholesterolemia and hypertriglyceridemia, the median time to onset is around 15 days within 2 weeks. For myself, I do check the lipid panel at baseline for these patients and repeat fairly early on within 2 weeks of therapy and continue to monitor closely thereafter. For edema, peripheral neuropathy and CNS side effects, the median time to onset is around 2 to 4 months. And so really what you're seeing is that most adverse events are occurring within 4 months of starting treatment.

In terms of the management of these adverse events, on the far left side for hyperlipidemia, most patients did require concomitant lipid-lowering therapy like statin but did not require dose modification or discontinuation because of these side effects. In the middle, most CNS adverse events and also weight gain were manageable without medical intervention. CNS adverse events in patients treated with lorlatinib mostly resolved with dose modification when needed. So again, dose reduction is important to consider and I would say this is consistent with my own clinical experience as well. Weight gain, on the right-hand side, mostly was managed with lifestyle modifications. And I think as we have even longer follow-up data from CROWN in the years ahead, we'll continue to learn more and more about how to optimally manage the longer-term adverse events associated with therapy.

Now also in the metastatic ALK-positive non-small cell lung cancer space, we saw updated data presented at the ESMO Congress in September for NVL-655. This is now called neladalkib. NVL-655 is a fourth-generation ALK selective inhibitor that is also brain penetrant. This agent was also developed to have coverage against a broad spectrum of single ALK mutations and compound ALK mutations that can cause resistance to early generation ALK inhibitors as well as lorlatinib. The data presented were from the global trial ALKOVE-1. There were already over 100 patients treated as of this data cutoff and notably most of these patients had already received lorlatinib. Remember right now we don't have an FDA approved targeted therapy option for patients once they've already received lorlatinib. In ALKOVE-1, as of these data presentation, the overall response rate to NVL-655 was 38%. In patients who had received prior lorlatinib, the response rate was 35%. And that response rate rose higher in those patients known to have baseline ALK resistance mutations after prior ALK TKI exposure. This agent is also known to have CNS activity in patients with brain metastasis.

Here are the preliminary safety data that were presented. These were overall consistent with the ALK-selective design of NVL-655. Only 2% of patients required treatment discontinuation due to a treatment related adverse event, 15% required dose reduction. And in the dose escalation portion of the study, the maximum tolerated dose was actually not reached. And we have a recommended Phase II dosing that's been presented and the trial is ongoing.

So what is my take on the wealth of these data? Multiple second and third-generation ALK TKIs are FDA-approved and listed as NCCN category 1 recommendation as first-line therapy for metastatic ALK-positive lung cancer. You just heard about ensartinib as being the latest FDA-approved one but it is a second-generation ALK inhibitor. The 5-year analysis from CROWN trial affirmed lorlatinib as a standard of care first-line therapy for this patient population with compelling progression-free survival and intracranial outcomes data and no new safety signals identified. And then the fourth-generation ALK TKI, NVL-655, or neladalkib, is also demonstrating quite encouraging activity and tolerability in a heavily pretreated patient population. This agent is being evaluated in now both TKI-pretreated as well as TKI-naïve patients.

There are many remaining questions. I have just shared a couple of those here. First, how will the prolonged progression-free survival outcomes that we're seeing now with the higher generation TKIs ultimately impact the overall survival outcomes for patients? And then, what is the landscape of the mechanisms of resistance to first-line therapy when third or fourth-generation ALK TKIs are being used? Because that could affect subsequent treatment options.

Now in early-stage ALK-positive lung cancer, we have one ALK TKI that is FDA approved for adjuvant use post-surgery and that is alectinib. This approval was based on the results from the Phase III ALINA trial, which enrolled patients with resected Stage IB to IIIA ALK-positive non-small cell lung cancer. And participants were randomized to receive either alectinib for up to 2 years or 4 cycles of platinum-based chemotherapy, the older standard of care. And DFS per investigator was the primary endpoint.

These results were published in The New England Journal of Medicine over the past year. So in patients with Stage II to IIIA disease the hazard ratio for patients with Stage II to IIIA disease was 0.24 in favor of adjuvant alectinib versus chemotherapy. And then in the intention to treat population, including those patients with resected Stage IB disease, hazard ratio for disease recurrence or death was 0.24. These were immediately practice changing results and they led to adoption of alectinib as standard adjuvant therapy.

At the recent WCLC, Professor Horinouchi and colleagues presented further safety data from the ALINA trial. The adverse event profile of alectinib was consistent with the prior literature. You can see the most common adverse events in the tornado plot. The median dose intensity of adjuvant alectinib was 99.4%, so quite high, good to see. And 5% of adverse events led to treatment withdrawal.

The most frequent adverse events of alectinib tended to occur mostly during the first month of therapy and adverse events of longer duration were typically low-grade in severity. They were typically manageable in the trial and did not require treatment discontinuation. So adjuvant alectinib is standard of care for patients with resected ALK-positive non-small cell lung cancer. This is approved by both FDA and European Medical Agency and it's listed as the NCCN category 1 recommendation. And it really underscores that biomarker testing is now essential for all stages of non-small cell lung cancer, not just in the metastatic Stage IV setting.

A few of the several remaining questions are highlighted here. One, what is the optimal duration of adjuvant ALK inhibitor? Is it 2 years as was done in the ALINA trial? Should it be longer or even shorter? We don't know. Who should receive adjuvant chemotherapy prior to or together with an ALK inhibitor? Remember the trial itself randomized patients to either alectinib or chemotherapy. So this is an unanswered question. And of course, is there a role for an ALK inhibitor in the neoadjuvant or perioperative setting or in patients with unresectable Stage III lung cancer after they've received concurrent chemoradiation? Those are all open questions at this time.

Next, I will review the data for a distinct molecular subset of non-small cell lung cancer harboring ROS1 fusions. Briefly, the current NCCN guidelines for patients who have metastatic ROS1 lung cancer are to start with a ROS1 TKI as first-line treatment. So there are 3 currently listed as preferred ROS1 inhibitors. These are crizotinib, entrectinib and repotrectinib. As a background, crizotinib and entrectinib have been approved for a few years now already. These are what we consider to be the first-generation ROS1 inhibitors. And each of these has been evaluated in Phase I/II clinical trials showing response rates and PFS as shown. So for crizotinib, in the PROFILE 1001 trial, we saw a response rate of 72% and median progression-free survival of 19.3 months. And then in integrated analysis of 3 Phase I/II trials, entrectinib showed a response rate of 68% and median progression-free survival of 15.7 months. I would say that these are largely comparable data for systemic efficacy but one of the distinguishing factors between these 2 is that entrectinib has shown CNS activity in patients with brain metastasis whereas crizotinib has minimal CNS activity.

The more recent one to be incorporated into the guidelines was repotrectinib. So repotrectinib is different. It's a next-generation TKI that targets ROS1 NTRK. In fact, we're going to come back to repotrectinib later on in this talk when we discuss TRK fusion positive lung cancer. At this time, repotrectinib is the only FDA-approved next-generation ROS1 inhibitor for metastatic ROS1 lung cancer. And this approval was granted based on the data from the global Phase I/II trial called TRIDENT-1. At ASCO meeting last year, we heard the updated data from that trial with longer follow-up. And it continued to show good efficacy in patients with metastatic ROS1 positive lung cancer who were TKI naïve including CNS efficacy with an intracranial response rate of 89%. Of note, the median progression-free survival here among TKI naïve patients treated with repotrectinib was 35.7 months. But this is longer than what we had seen previously with crizotinib or entrectinib where the median progression-free survival was historically more in the 16- to 19-month range.

At that presentation, we also had a look into the treatment patterns in patients who had received repotrectinib as first-line therapy. And what's interesting here is that many patients, indeed 24 out of 28 patients, continued repotrectinib beyond disease progression. And although the median duration of treatment beyond progression was around 2.8 months, about half of these patients were able to continue repotrectinib for more than 3 months beyond progression. And some of these patients, what the plot on the left-hand side shows is that they received local therapy. So you do wonder about the subset of patients who might have had more limited site disease progression where they could receive local therapy to address that limited disease progression and then otherwise continue on the same TKI. Certainly this is a practice that we do adopt in the clinic these days for carefully selected patients.

In terms of subsequent therapy, some of these patients received a ROS1 inhibitor. Another subset of patients received chemotherapy either with or without immunotherapy. So although currently repotrectinib is the only approved next-generation ROS1 inhibitor, we have other next-generation ROS1 TKIs on the horizon as well that you're going to hear more and more about because these are showing quite encouraging data. So I wanted to make sure to go over these. Taletrectinib is one of the next-generation ROS1 inhibitors. And it's been evaluated in a Chinese Phase II trial, TRUST-I, and subsequently in the global Phase II trial, TRUST-II. At WCLC, Dr Jeffrey Liu presented the preliminary efficacy and safety data from the global Phase II trial. Among TKI-naïve patients, the confirmed response rate with taletrectinib was 85.2%. And among TKI pretreated patients, so these patients had received a drug like crizotinib, for example, the confirmed response rate was 61.7%.

A key point to highlight here is that each ROS1 inhibitor has a unique safety profile. So we really have to become familiar with the side effect profile of each drug in a distinct manner. In TRUST-II, 37% of patients who received taletrectinib had a treatment emergent adverse event requiring dose reduction. And 7.5% had a treatment emergent adverse event resulting in discontinuation. The most common adverse events were increases in liver enzymes and diarrhea and nausea as you can appreciate from the table. Of note, the prior ROS1 inhibitor that I mentioned, repotrectinib, is a potent ROS1 NTRK inhibitor and so neurologic treatment related adverse events are frequent. That includes dizziness, paresthesia and dysgeusia. And these are felt to be related to TRK inhibition by the TKI. With taletrectinib, the rates of these neurologic adverse events were relatively lower although still occurring in more than 10% of patients. So the side effect profile I think is going to be an important consideration and a distinguishing factor amongst the next generation ROS1 inhibitors.

We've also seen pooled efficacy data from the Chinese and global Phase II trials. These results were published very recently in the Journal of Clinical Oncology. And what I wanted to bring to your attention is the median progression-free survival here in the TKI-naïve population, on the right-hand side, of 45.6 months. Again, significantly longer than what we are used to seeing with the first-generation ROS1 inhibitors like crizotinib and entrectinib.

I should add that this agent, like repotrectinib, has shown activity against brain metastasis and also relevant to patients who may already have received prior crizotinib or entrectinib because they were diagnosed earlier. For example, activity against ROS1 resistance mutation that can cause resistance to first-generation TKIs like ROS1 G2032R. That's a mutation that we see recurrently in patients who experience disease progression on crizotinib or entrectinib.

The last next-generation ROS1 inhibitor that I'm going to cover today is called zidesamtinib, formally called NVL-520. This is a brain penetrant next-generation ROS1 selective inhibitor that is being evaluated in the global multicenter trial, ARROS-1. So at ESMO Congress in 2024, the updated preliminary efficacy and safety data were presented. Really encouraging activity for this agent in heavily, heavily pretreated patients including in those patients that had received prior repotrectinib or lorlatinib. CNS activity was also observed in patients who had brain metastasis.

Of note, zidesamtinib was specifically designed to be selective against ROS1 and to spare targeting of the TRK kinases. Because of the knowledge that TKIs like entrectinib and repotrectinib inhibit both ROS1 and TRK and because of that patients can experience side effects related to TRK inhibition. And consistent with that design for zidesamtinib, the safety profile observed has been quite favorable without significant neurologic toxicities here. No treatment related adverse events resulting in discontinuation and only 8% of patients needing dose reduction due to treatment related adverse events. Maximum tolerated dose for this agent was not reached. And the recommended Phase II dose was determined for once daily dosing. So this drug is continuing to be evaluated in metastatic ROS1 lung cancer. You're going to hear more about this going forward and we'll hear about efficacy both in TKI-pretreated patients as well as TKI-naïve patients that are newly diagnosed.

How are we going to put these data together? Currently repotrectinib is the only FDA approved next-generation ROS1 inhibitor. That said, the landscape of first- and later-line-use ROS1 inhibitors will continue to actively evolve in the near future with emerging next-generation agents. I think this is definitely a really important and exciting space to continue to keep an eye on. And considerations in selecting the first-line therapy as we have more and more options for patients will include both systemic and CNS efficacy as well as tolerability and access to therapy. I have shared here on the left-hand side a figure that demonstrates the relative levels of systemic efficacy on the top, the CNS efficacy in the middle and neurologic side effects that were selected at the bottom. These were reported across of course different clinical trials evaluating ROS1 inhibitors, so important caveat there about cross-trial comparisons. But, in general, I think we are achieving longer progression-free survival that are overall efficacy with the next-generation ROS1 inhibitors with distinct adverse event profiles.

Now moving into RET fusion space, another distinct molecular subset for our patients. We have 2 RET inhibitors that are FDA approved at this time and recommended by NCCN as first-line therapies for metastatic RET rearranged lung cancer. These are selpercatinib and pralsetinib. These agents were developed in parallel and I've summarized the key efficacy data here from the LIBRETTO 001 trial for selpercatinib and the ARROW trial for pralsetinib. The bottom line is that both TKIs have shown good systemic efficacy and also activity against brain metastasis.

This past year Dr Perol and colleagues published in Journal of Clinical Oncology the CNS efficacy data from the LIBRETTO-431 trial. This was a randomized controlled Phase III trial that compared selpercatinib as first-line therapy versus chemotherapy with or without pembrolizumab as first-line therapy for patients with metastatic RET fusion positive lung cancer. It was a positive study in favor of selpercatinib using RET targeted approach. But what this publication and the CNS efficacy data published therein illustrated is that among patients with brain metastasis at diagnosis and no prior CNS radiotherapy, selpercatinib was able to induce an intracranial response rate of 93% with majority having durable intracranial responses. Furthermore among patients treated with selpercatinib, who did not have brain metastasis at baseline, the 12-month cumulative instance rate for CNS progression was only 1.1% with a 12-month CNS progression-free survival rate of 91.8%. These rates were in significant contrast to what was seen among patients in the control arm, those who received chemotherapy plus pembro. There the 12-month cumulative instance rate for CNS progression was 14.7%, significantly higher than the 1.1%. So again, selpercatinib and pralsetinib are both FDA approved and recommended first-line therapies for metastatic RET fusion positive lung cancer. Both have demonstrated CNS efficacy. The CNS outcome analysis from the LIBRETTO-431 trial further support that a brain active TKI like selpercatinib can delay CNS progression and may prevent new brain metastasis. Together with the data for agents like lorlatinib in ALK-positive lung cancer that we reviewed earlier, I think these data are emphasizing for us the tremendous benefits of developing a brain active targeted therapy that can really mitigate the risk of brain metastasis, which pose a significant burden for patients and families.

NTRK1, NTRK2, NTRK3 fusions, TRK fusions altogether occur in less than 0.3% of patients with non-small cell lung cancer. So really very rare but they are important to look for and identify because we actually have multiple FDA approved TRK inhibitors.

Until recently we had 2 approved TRK inhibitors. These are entrectinib and larotrectinib. They are both approved actually for adult and pediatric patients who have TRK fusion positive advanced solid tumors. So regardless of the tumor type, as long as the tumor is known to have an oncologic TRK fusion, whether you're an adult or pediatric patient, these TKIs are approved. We saw updated efficacy and safety data for both entrectinib and larotrectinib over the past year with longer follow-up in trials.

So starting with entrectinib, these results were published by Dr Cho and colleagues last year. The median progression-free survival in patients with metastatic TRK fusion lung cancer was 28.0 months, median overall survival for these patients was 41.5 months with a median follow-up there of 26 months. As a reminder, entrectinib is brain active. The intracranial response rate for patients with baseline brain metastasis with TRK fusion positive lung cancer was 64% and intracranial progression-free survival was 33 months.

And then at WCLC, the larotrectinib longer follow-up data were presented. Larotrectinib continues to show good efficacy with median progression-free survival of 22 months, median duration of response 34 months and median survival of 39 months. And this is with a survival follow-up median of 33 months. Larotrectinib has also shown activity against brain metastasis. And then safety update for larotrectinib continued to support good tolerability overall. Mostly low-grade treatment related adverse events. Very low rates of treatment discontinuation or severe adverse events with toxicity profile.

And then in June last year, a third TRK inhibitor entered the landscape becoming FDA approved for again both adult and pediatric patients with TRK fusion positive solid tumors. This is repotrectinib that we referred to earlier. Remember that this is a next-generation TKI that inhibits both ROS1 and TRK. In the TRIDENT-1 study, there were cohorts of patients enrolled with TRK fusion positive cancers. And here to confirm the overall response rate was 50% and the median progression-free survival was 7.4 months. Importantly there can be resistance to prior TRK inhibitors with on-target TRK acquired mutations. And repotrectinib was able to demonstrate activity in these pretreated patients with known TRK resistance mutations. So that's an important advance to have a next-generation inhibitor that can be used in TKI-pretreated patients.

Now larotrectinib, entrectinib and repotrectinib are all NCCN guideline-recommended first-line therapies for patients with metastatic TRK non-small cell lung cancer. And then with longer follow-up, both entrectinib and larotrectinib are continuing to show significant clinical activity and favorable tolerability. And repotrectinib is a next-generation TKI that has shown efficacy in both TKI-naïve and TKI-pretreated patients. Given the durable benefit from these agents, it's becoming even more critical to continue to assess TKI-associated toxicities and optimal management strategies.

Last but not least, we are going to review NRG1 fusions. We didn't have to review this in prior CME talks because there didn't use to be an FDA-approved targeted therapy for this subset but now there is. NRG1 fusions are also rare. They are also found in less than 0.3% of all solid tumors including non-small cell lung cancer but now we have, as of December 2024, we have an FDA-approved targeted therapy and the label is for patients with NRG1 fusion positive advanced non-small cell lung cancer or pancreatic adenocarcinoma. So what is this agent? The drug is zenocutuzumab. It's a mouthful. Zenocutuzumab is a bispecific antibody targeting HER2 and HER3. This agent is dosed intravenously as an infusion every 2 weeks. It was investigated in the Phase II trial called eNRGy. And you can see the waterfall plot here on the right-hand side. Different colored bars represent patients with distinct tumor types all with NRG1 fusion. You can appreciate that there were nice deep responses across the board. Specifically, among patients with NRG1 fusion positive non-small cell lung cancer, the overall response rate was 29%. It is a tolerable drug. You can see the adverse event profile on the right-hand side in the table as well as the dose modification rates specified.

So zenocutuzumab represents a new standard of care. It is an FDA approved treatment option for patients who have been diagnosed with advanced NRG1 fusion positive non-small cell lung cancer. And therefore we must look for NRG1 fusions in patients with non-small cell lung cancer going forward. I will acknowledge that the overall response rate is more modest relative to other targeted therapies in lung cancer like osimertinib or lorlatinib that we talked about. And therefore I would reserve zenocutuzumab not as first-line therapy but as later-line therapy for patients at this time.

Therapeutic Approaches Targeting HER2, MET, BRAF and KRAS G12C — Joel W Neal, MD, PhD

DR LOVE: Subsequent to the recording of this interview, telisotuzumab vedotin received accelerated FDA approval on May 14, 2025, for the treatment of adults with locally advanced or metastatic, nonsquamous non-small cell lung cancer with high c-Met protein overexpression (greater or equal to 50% of tumor cells with strong [3+] staining), as determined by an FDA-approved test, and who have received a prior systemic therapy.

DR NEAL: Hello, I'm Joel Neal. I'm at Stanford University, director of the Thoracic Oncology Program here and a thoracic medical oncologist. Today it's my pleasure to share with you updates in some of the targeted therapies for non-small cell lung cancer including ERBB2/HER2, MET alterations in lung cancer, BRAF mutations and some emerging data in KRAS mutant non-small cell lung cancer.

Here's an overview of our agenda for today. I won't dwell on this but provide it for reference. We'll be going through all of these papers and dive in a little more detail on some of these that are new and emerging.

First of all, we'll start off with ERBB2 mutations, also known as HER2 mutations, in non-small cell lung cancer. There's a variety of different mutations that we observe, including most commonly, as you can see in the red box, the exon 20 insertion mutations. The most common of these is the 772 duplication YVMA. You can see that makes up almost a third of observed non-small cell lung cancer with exon 20 insertions, but there's a variety of other mutations which could be activating including the point mutation over there on the far left, S310F. As we think about developing targeted therapies for those, some of the targeted therapies that we have work in an extracellular way on the outside of the cell, particularly antibody-drug conjugates. Others are more classical tyrosine kinase inhibitors that work on the tyrosine kinase domain. So we'll be talking about both of those today.

First, we'll talk about T-DXd, also known as trastuzumab deruxtecan for HER2 mutant non-small cell lung cancer. So we'll be talking about both HER2 overexpressed protein expression and HER2 mutant. But first starting off on the established data for HER2 mutant non-small cell lung cancer last presented by Pasi Janne at ASCO 2024. This was the DESTINY-Lung02 study. As you can see, patients with metastatic HER2 mutant non-small cell lung cancer incorporating most of the mutations we just reviewed with more than one prior anticancer therapy were treated with trastuzumab deruxtecan either at the 5.4 mg/kg or at the slightly higher 6.4 mg/kg dose. What we can see over on the right is that the response rates range from 50 to 56% for patients depending on dose. Progression-free survival 10 to 13 months and overall survival not different between the 2 different dose arms, 19 versus 17 months. Based on this, the current FDA approved dose in HER2 mutant non-small cell lung cancer after 1 prior line of therapy is the 5.4 mg/kg dose.

Next we'll move on to HER2 overexpression or immunohistochemistry positive non-small cell lung cancer and lung adenocarcinoma. There are a number of different articles demonstrating the positivity of HER2 expression in non-small cell lung cancer may be as low as 8%, as high as 30% depending on the assay methodology. In addition in the table below, it's demonstrated that there's many different ways that you can do scoring. There's a standard breast cancer scoring, gastric cancer scoring and the more classical H-score. And there's fairly decent concordance especially within the 2+ and 3+ realm between these different tests. So if you have a home developed test against breast cancer or gastric cancer that should be sufficient for using for detecting HER2 positive lung adenocarcinoma.

Trastuzumab deruxtecan was also tested here in the DESTINY-Lung01 study. We can see that there were 2 different cohorts at the top of HER2 overexpressing non-small cell lung cancer at the 2 different dose levels. And patients were included with either 2+ or 3+ immunohistochemistry-positive. When we look at the response rates, the response rate was lower than we see for HER2-mutant non-small cell lung cancer, 26% and 34% depending on dose levels, actually slightly lower for the higher dose, with the duration of response around 6 months for both groups. Looking at the progression-free survival here, we can see that progression-free survival for the overall cohort of 5.4 mg was 6.7 months, overall survival around 11.2 months. What I thought was interesting about this is this HER2 overexpression seems to happen independently of many of the molecular alterations we find in lung cancer. So at the bottom you can see that a few of the overexpressed tumors were EGFR mutant, many more actually in K-RAS mutations and there were other alterations too including HER2 amplification as tested by FISH, which sometimes overlapped with overexpression but sometimes did not. So I would encourage people to use the IHC test because there is an indication for trastuzumab deruxtecan for HER2 positive cancers, pan-cancer and that includes lung cancer.

We looked at other data here. So this was presented at World Conference Lung Cancer 2024 by David Blanchard. And this study was interesting because it included more patients in part 1 of the T-DXd monotherapy, more patients with EGFR mutant non-small cell lung cancer in a broader population that had HER2 overexpression. So when we look at the data here, very similar for the 5.4 mg/kg dose as what we just saw in the last DESTINY study. Progression-free survival around 8 months, median overall survival around 17 months. And some of the side effects that we'll get into on the next slide include many chemotherapy side effects from the TopA-1 payload that's delivered from the antibody-drug conjugate including nausea, fatigue, anemia. Here they didn't see pneumonitis but that's also something we'll go into in a minute.

When we look at safety overall for trastuzumab deruxtecan, it's the same as in other indications. But one thing that's unique maybe that pneumonitis has a slightly higher risk in non-small cell lung cancer. Total risk of pneumonitis might be as high as 15% across many of these studies and this is adjudicated with centralized groups that looked and tried to sort out pneumonitis from disease progression from just regular pneumonias that patients can get. So adjudicated pneumonitis was somewhere between 15 and even as high as 20%. There may be slightly higher risk for patients who had had immunotherapy within the last 3 months. Overall safety of the drugs though you can see on the far left include many chemotherapy side effects probably from the payload, common things that we're good at managing, and a low risk of stomatitis. I will note that alopecia is common with this, which is unique compared to most of our first-line treatments in lung cancer, which often include pemetrexed. So many patients have AEs but these are felt to be fairly manageable and this is an IV once every 3 week dosing and schedule.

Moving on, there's exciting new data of HER2 directed tyrosine kinase inhibitors. So there have been many attempts to develop these. Even drugs back in the day such as afatinib, which is approved in EGFR mutant lung cancer, has some off-target activity in HER2 mutant non-small cell lung cancer but seem modestly active. There is some TKIs that are active in breast cancer that are approved but unfortunately these are not quite as active against these exon 20 insertion lung cancer mutations.

So in this study, the Beamon LUNG-1 study, a drug called zongertinib was tested at 2 different dose levels, 120 mg and 240 mg, with expansion at the 120 mg dose in patients with tumors with a tyrosine kinase domain mutation, patients with the same mutation that were previously treated with a HER2 directed antibody-drug conjugate generally trastuzumab deruxtecan, when it was available locally, and also patients with tumors with a non-tyrosine kinase domain mutation such as that S310F. Over on the far right, I've summarized the data for you. In cohort 1, the response rate was 71%, disease control rate 96%, duration of response of the 71% of responders 14 months and progression-free survival exceeded a year, 12.4 months. Looking at the other 2 cohorts, the numbers were fairly small and they haven't reported the mature data yet. Response rates were somewhat more modest after previous treatment with a HER2 directed ADC and for the nontyrosine kinase domain mutations. So for those other random mutations only a 30% response rate but still many patients responded. So I think we still have questions about exactly which of these mutations are most suitable for a drug like zongertinib. But I think these data, especially looking at cohort 1, I think back to the days of EGFR mutant lung cancer and the original data for gefitinib and erlotinib and this response rate in progression-free survival is actually better than we saw for the original EGFR TKIs. So this is a solid targeted therapy not yet FDA approved, not yet available, but certainly on the runway.

Here's the progression-free survival curve showing over 12 months of progression-free survival, which is very exciting. And then there does look like there's some intracranial activity as well with these drugs. We know that all lung adenocarcinomas have a decent risk of brain metastases especially those with targeted mutations. And when I think about HER2-mutant non-small cell lung cancer I think much of the biology is fairly similar to classical EGFR-mutant lung cancer or EGFR exon 20 insertion non-small cell lung cancer, which should not be confused with these exon 20 insertion mutations. But we do see some responses in patients with measurable brain metastases, 27 patients measurable, response rate 41%. Yes, this is lower than the overall response rate but still demonstrating possible intracranial efficacy. And I do wonder about the different dose levels and whether the higher dose might have more intracranial efficacy at 240 mg.

There's another TKI. This drug BAY for HER2-mutant lung cancer. This was a cohort of TKI and other trastuzumab based therapy naive patients with lung cancer and HER2 insertion mutant disease. Demonstrated a response rate overall of around 70%, so a partial response rate 70%, a couple of complete responses on top of that, with a duration of response of 8.7 months. Progression-free survival though at 7.5 months, at least as of this report, numerically looks lower than that cohort 1 we saw from zongertinib exceeding 12 months. Although I will note that most of the patients down here on the waterfall plot did seem to have some degree of response. So it's hard to do cross-trial comparisons particularly between different Phase II clinical trials with different selections conducted in different places. But I think both of these drugs look highly active and much more active than the drugs we have tried historically as far as TKIs in this tumor type.

What about safety and tolerability? While most of these have side effects that we expect from tyrosine kinase inhibitors in general, most notably diarrhea, rash and some LFT abnormalities at the top of the list. Zongertinib numerically again seems to have fewer overall side effects with BAY drug having 90% diarrhea going down from there. Zongertinib only 50% of patients having diarrhea especially at the 120 mg dose. And then looking down to the bottom, fewer Grade 3 events for zongertinib, fewer dose reductions for zongertinib. So again, I caution people to not think about cross-trial comparisons, but it looks like zongertinib may be more tolerable and potentially more effective.

So in conclusion from this section the antibody-drug conjugates, especially trastuzumab deruxtecan, remains FDA approved for ERBB2 or HER2 mutant non-small cell lung cancer following prior therapy. We're thinking about its usage in the front-line setting and that would be as a single agent, not in combination with other chemotherapy or with immunotherapy, but thinking about its use in the first-line setting but currently it's approved in the later-line setting. We can think about HER2-positive non-small cell lung cancer with any other molecular alteration and those patients being a candidate possibly for trastuzumab deruxtecan as well. And there is an FDA approved pan-tumor indication for that. And the HER2 TKIs are emerging. Very exciting data from just last week presented by John Heymach about zongertinib. It appears more effective and tolerable so far and we'll see about other drugs that are emerging because there are indeed many other emerging HER2 TKIs in development. They may have different safety profiles, tolerability profiles and we'll keep an eye on CNS penetration too. I'm also hearing about HER2 bispecific antibodies and HER2 bispecific antibody-drug conjugates. So many more tools in the pipeline that we can see in investigation in the future.

Moving on to MET exon 14 mutations in non-small cell lung cancer. These are fun because for many, many years we had looked for MET alterations in lung cancer and we've been looking in the exons directly in the direct exon place. But these mutations are actually not in an exon. They're in the splice site just immediately prior to exon 14. So if you sequence whole exomes, you actually don't find them. You find splice mutations that drop out exon 14. And what this does is prevent degradation from MET from the cell surface resulting in mass activation of MET. So it's basically the same as overexpression on the cell surface happening on a genetic level where MET is being produced but not degraded because of aberrant splicing. So it's worth keeping in mind that this is wild-type MET for the most part. This degradation domain doesn't have much to do with the tyrosine kinase domain. So these are not really activating mutations in the tyrosine kinase, they're overexpression mutations.

So capmatinib is currently approved for MET exon 14 non-small cell lung cancer based on the GEOMETRY study. In first line therapy, it does seem to be somewhat more sensitive to non-small cell lung cancer with response rates pushing 70% progression-free survival over a year, overall survival almost 2 years as compared to in the same study when patients with prior treatment received capmatinib, response rate lower at 44%, progression-free survival half as much 5.5 months and overall survival numerically less. So even though chemotherapy and potentially immunotherapy can be active in that exon 14 non-small cell lung cancer, particularly in patients with PD-L1-negative disease and not a smoking history, I would definitely recommend MET TKIs in the front-line setting based on potential of more efficacy.

Tolerability. Peripheral edema tops the list followed by nausea, vomiting, creatinine things and LFT things. I would say in my experience the dose-limiting toxicity is almost always peripheral edema. And I've had a number of patients to dose reduce to three-quarters dose or half-dose. Ben Creelan at Moffitt as well as a couple of our patients have put together a hypothesis and tried SGLT2 inhibitors. I don't have any data to share with you, but if anybody out there has any data or tried these — I think they can help with the MET-related edema and really other things don't. So furosemide doesn’t help, compression stockings barely help, patients can't lie in bed with their feet above their heart for a certain amount of time. It's really kind of a puffy, refractory edema that's really hard to treat. So if anybody out there tries the SGLT2 inhibitors, any of them are fine, let us know.

Another type of MET alteration in lung cancer is MET overexpression. First, MET expression protein expression at least has been quite variable. And there's a number of different antibodies that have been tested but MET expression in non-small cell lung cancer seems highly expressed when you just look by immunohistochemistry and doesn't seem to be a strong predictor of response to therapies. So MET IHC, I think there's still some story about how do we define that IHC there. On the other hand, MET amplification — so looking truly for multiple MET genes as compared to the SEP7, the centromere, at looking for a high ratio or looking at next-generation sequencing or potentially circulating tumor DNA. Sometimes they can say, they look like many more copies of MET than everything else in the DNA. So MET amplification does look like a driver.

Telisotuzumab vedotin or Teliso-V, for MET amplification looks active with overall response rates in the 35% for MET-high, 23% for MET-intermediate and waterfall plots that look like there are responses in many but not all patients. And when we look in the study, progression-free survivals in the 5- to 6-month range and overall survivals in the 14-month range for this. So I think Teliso-V after being evaluated by the FDA for a while is being considered in this indication of MET amplified non-small cell lung cancer as an antibody-drug conjugate that may be active here.

When we look at side effects of this, in addition to the chemotherapy side effects again we see the peripheral edema and then uniquely probably because of the vedotin payload, peripheral sensory neuropathy that can be significant and sometimes persistent over time even after stopping the drug.

So in conclusion for MET lung cancer, for MET exon 14 mutant non-small cell lung cancer, capmatinib and tepotinib are approved and preferred first-line therapies right now. Teliso-V has an emerging role in MET gene amplified lung cancer. And MET protein IHC remains of uncertain significance. There's a lot of other drugs that are MET directed including both antibody-drug conjugates and tyrosine kinase inhibitors in development now.

Next we'll briefly touch on BRAF. So BRAF, there's 3 different classes of mutations. The most common in non-small cell lung cancer and also the only one that's currently actionable is the BRAF V600E mutation. The other classes are either kinase dead and don't signal through BRAF at all or kinase active but we don't have ways to target them right now. So all of these other BRAF mutations when we see them we're not exactly sure what to do besides maybe give standard treatments that we would give for otherwise mutation negative non-small cell lung cancer.

Encorafenib and binimetinib are emerging for this both in previously treated and treatment-naive patients with response rates in 75% for treatment naive, 46% for previously treated. And good-looking progression-free survivals. Duration of progression-free survival looking around 30 months actually in the first-line setting, 9 months for previously treated keeping in mind that dabrafenib and trametinib are also approved in non-small cell lung cancer in the same indication. One of the advantages of encorafenib/binimetinib seems to be not seeing the fevers that we see that are sometimes associated with dabrafenib as well as generally a slightly more favorable side effect profile. Overall survival had not been reached as of the previous presentation by Greg Riley at ESMO in 2024 but looks favorable.

So encorafenib and binimetinib are FDA approved reasonable alternative to dabrafenib/trametinib for lung cancer, also used in melanoma and both are approved in that setting. And then the Type II and the Type III BRAF mutations currently aren't actionable but options for these are in development in clinical trials.

Finally, we'll move on to KRAS mutations in non-small cell lung cancer first starting with KRAS G12C mutations but then touching at the very end about brand new data in KRAS G12D mutations. So KRAS G12C mutations in lung cancer comprise around 40% of all KRAS mutations, are often smoking associated and up until recently had not been actionable because KRAS can't be directly targeted in the GTP binding pocket. Instead allosteric targeting methods need to be used. I'll point out that KRAS G12D is often less smoking associated and has the same challenges about targeting. Now the G12C inhibitors took advantage of the cysteine residue. The cysteine residue allows covalent binding of small molecules and therefore targeting. So that was easier to target. And there are 2 drugs that have been used, adagrasib as well as sotorasib. So adagrasib for KRAS G12C in the KRYSTAL-12 study overall response rates were 30% for adagrasib as compared to docetaxel around 10%, which is how we expect it to perform, with waterfall plot showing response of the majority of patients after prior therapy. So this is following chemotherapy or immunotherapy or the combination. Looking again at progression-free survival. Progression-free survival 5.5 months for adagrasib. Significantly better than docetaxel, but if we think back to what I said about drugs like zongertinib in the first generation EGFR TKIs, we're seeing progression-free survivals of 11 to 12 months, seeing response rates more in the 70%. So these drugs are definitely hitting the target but not as highly active as some of the other small molecule targeted therapies that we have.

There's quality of life analysis for this approved drug though and compared to docetaxel quality of life does seem to be better and these data presented at ASCO by Tony Mok with less, slower time to deterioration for adagrasib. We expect that for drugs that have a longer progression-free survival but also more tolerability than docetaxel especially when docetaxel is given in the 75 mg/m² every 3-week dosing.

Sotorasib, from this publication in lung cancer, also showed a more favorable side effect profile compared to the docetaxel with side effects. As you can see hotter and brighter colors, yellow, orange, red being patients more bothered by the side effects of treatment. And you can see that that persistently goes on from the beginning all the way through the far right as treatment continues on. Whereas sotorasib, patients are bothered by treatment more in the first half of the therapy but then those side effects generally go away over time or become mild. So both of these drugs, adagrasib and sotorasib, look tolerable. The question though is, without a lot of activity can we combine them with other drugs in the first-line setting? Divarasib is another KRAS G12C inhibitor but came later into emergence with a progression-free survival by itself in all patients of 13 to 18 months numerically looks pretty good. Response rates 55 to 59%. But can it be combined with immunotherapy? So in this second-line study it was combined with atezolizumab and indeed response rates for no prior KRAS G12C inhibitors of 55 to 61%, many patients had shrinkage of tumor. Hard to interpret these data when we're comparing 2 therapies together though in a second-line setting of what we would expect in historical controls. But it looks like it can be tolerated and safety was okay.

Olomorasib is also a G12C inhibitor and in this cohort including non-small cell lung cancer patients, it was actually boldly given in the front-line setting together with pembrolizumab, pemetrexed and platinum. This was only 21 patients but response rates looked favorable. Of course this is first-line untreated patients so we expect them to have good responses. And when we think about side effects, we worry especially about LFT abnormalities, which had been a problem with immunotherapy plus sotorasib and in part adagrasib, which looked common but less common than with either of those other 2 drugs. Patients are getting anemia. Patients are getting some LFT abnormalities. But mostly chemotherapy side effects. And I'll note that oftentimes these LFT abnormalities would get better when the olomorasib was held as opposed to the immunotherapy held suggesting that they were manageable, went away and dose reductions could help.

Moving on to the final and very exciting data presented by Kasey Arbour at AACR 2025. This is a novel drug, zoldonrasib. First time I've publicly said that. Zoldonrasib for KRAS G12 C non-small cell lung cancer. So zoldonrasib, again like I said, KRAS can't be really targeted in the pocket so they took advantage of a natural binding to another cellular occurring protein called cyclophilin A, which binds to a lot of things, and created a surface between cyclophilin A and the RAS(ON) stable confirmation, which created a tri-complex between the small molecule and these 3 proteins in a covalent interaction that prevented RAS from signaling downstream. In zoldonrasib for KRAS G12D, the response rates overall were 61%. Median time to response 1.4 months and time on treatment only 2.6 months as of this very, very early presentation. But as we can see from the little arrows over on the left on the waterfall plot and the arrow heads over on the right on the swimmer's plot, most of the patients are still on treatment. So as these data mature, we'll expect to see these progression-free survival numbers and things like that hopefully be favorable in the small population of only 18 patients.

Side effects from that seem tolerable. Usual TKI side effects, nausea, diarrhea, vomiting, AST/ALT increase but all less than 50%. So look tolerable at least across all of the patients, the 90 patients treated so far, with the 1200 mg dose on whom safety have been reported.

So in conclusion, adagrasib and sotorasib are approved for KRAS G12C. In my opinion, adagrasib looks modestly more effective and is slightly favored. Divarasib and olomorasib may be more compatible with immunotherapy and possible front-line combinations. And zoldonrasib is a novel KRAS G12D inhibitor with promising efficacy. There's a lot of other RAS(ON) inhibitors including G12C RAS(ON) inhibitors, Pan-RAS inhibitors and other G12D inhibitors that are currently in development and in clinical trials that we'll keep an eye on.

Thank you very much.